The transepithelial potential difference (PD) is raised across cystic fibrosis (CF) respiratory epithelia. This raised voltage reflects active sodium absorption across a relatively chloride impermeable membrane. Because relatively little is known about the regulation of the rate of sodium absorption across mammalian airways, we assessed the possible contribution of aldosterone to the PD in normal and CF respiratory epithelia. Aldosterone excretion in five CF patients was 12.2 ± 0.9 μg/24 h, a mean value not different from normal control subjects (13.6 ± 1.5 μg/24 h,n= 5). Despite similar aldosterone excretion rates, nasal PD was more than 2-fold greater in the CF patients (-53.6 ± 6.4 mV) than normal subjects (-21.3 ± 1.4 mV). The effect of an aldosterone antagonist, spironolactone, on aldosterone excretion and nasal and rectal PD was evaluated in four CF patients and five normal subjects. During spironolactone administration, aldosterone excretion increased (2− to 4-fold) and rectal PD decreased in both groups. However, nasal PD was unchanged in each group (CF = −52.1 ± 4.3 mV pre, −53.6 ± 1.4 mV during; normal = −21.2 ± 3.1 mV pre, −21.6 ± 3.2 mV during). We conclude that neither increased aldosterone secretion rates nor organ sensitivity to aldosterone can account for the abnormally raised PD that characterizes the respira.